Research on the Prediction Method of Braking Rotation Angle for Remote-Controlled Excavator.

To calculate, analyze, and predict the rotation angle during the deceleration and braking process of large remote-controlled excavators, this article established a spatial coordinate system based on a simplified model of a hydraulic excavator's upper structure. Using the D-H parameter method, a mathematical model of the working device's center of gravity and its rotational inertia was established. Based on the characteristics of the excavator's hydraulic system and the relationship between brake torque variations, a prediction model was developed to forecast the stopping position (brake rotary angle) of the excavator's bucket after braking. Subsequently, the predicted results were validated using simulation and compared with existing experimental data to assess the accuracy of the model. The findings demonstrate that the predictive model exhibited high precision with minimal error. The utilization of this model enabled effective forecasting of the excavator's braking position changes, providing a theoretical foundation for the intelligent remote control of excavators.

[Effect of electroacupuncture of "Hegu" (LI4) and "Zusanli" (ST36) on intestinal sensitivity and motility in irritable bowel syndrome rats].

OBJECTIVE: To observe the effect of electroacupuncture (EA) of "Hegu"(LI4) and "Zusanli"(ST36)on changes of intestinal sensitivity and colonic motility and expression of colonic 5-hydroxytryptamine 3A receptor (5-HT3AR) in irritable bowel syndrome (IBS) rats, so as to reveal its mechanism underlying improvement of IBS. METHODS: A total of 40 neonatal Wistar rats were randomly and equally divided into normal control, model, LI4 and ST36 groups (n＝10). The IBS model was induced by mother-infant separation, acetic acid enema and colorectal distension (CRD). EA (2 Hz/100 Hz, a tolerable strength) was applied to bilateral LI4 and ST36 for 20 min, once every other day for 5 times. The Bristol stool form scale was used to assess the gastrointestinal function, and the latency and number of abdominal muscular contraction waves of abdominal withdrawal reflex (AWR) were used to evaluate the intestinal sensitivity and motility respectively. The immunoactivity of 5-HT3AR of the colon tissue was detected by immunohistochemistry. RESULTS: After modeling, the score of Bristol fecal form scale, number of muscular contraction waves and expression levels of colonic 5-HT3AR in the myometrium and mucosal layers were significantly increased (P<0.01), and the latency of muscular initial contraction wave was obviously shortened in the model group relevant to the normal control group (P<0.01). After the intervention, the increased Bristol fecal form score, number of muscular contraction waves and expression levels of 5-HT3AR in the myometrium and mucosal layers as well as the decreased latency of muscular contraction were reversed in both LI4 and ST36 groups (P<0.01, P<0.05). The effect of EA of ST36 was significantly superior to those of EA-LI4 in lowering Bristol fecal scale score and 5-HT3AR expression in the muscular layer (P<0.01), but obviously inferior to those of EA-LI4 in increasing the latency of of muscular initial contraction wave and down-regulating muscular contraction waves and 5-HT3AR expression in the mucosal layer (P<0.05, P<0.01). CONCLUSION: Both EA-LI4 and EA-ST36 can significantly improve the symptoms of abdominal pain and diarrhea, but EA-LI4 is better in suppressing intestinal high sensitivity, and EA-ST36 is better in promoting intestinal motility, suggesting a specificity of effect of acupoints of different meridians.

Spinal subpial delivery of AAV9 enables widespread gene silencing and blocks motoneuron degeneration in ALS.

Gene silencing with virally delivered shRNA represents a promising approach for treatment of inherited neurodegenerative disorders. In the present study we develop a subpial technique, which we show in adult animals successfully delivers adeno-associated virus (AAV) throughout the cervical, thoracic and lumbar spinal cord, as well as brain motor centers. One-time injection at cervical and lumbar levels just before disease onset in mice expressing a familial amyotrophic lateral sclerosis (ALS)-causing mutant SOD1 produces long-term suppression of motoneuron disease, including near-complete preservation of spinal α-motoneurons and muscle innervation. Treatment after disease onset potently blocks progression of disease and further α-motoneuron degeneration. A single subpial AAV9 injection in adult pigs or non-human primates using a newly designed device produces homogeneous delivery throughout the cervical spinal cord white and gray matter and brain motor centers. Thus, spinal subpial delivery in adult animals is highly effective for AAV-mediated gene delivery throughout the spinal cord and supraspinal motor centers.

Effect of Electroacupuncture at Different Acupoints on the Expression of NMDA Receptors in ACC and Colon in IBS Rats.

OBJECTIVE: To observe the effects of electroacupuncture (EA) at different acupoints on the expression of N-methyl-D-aspartate receptor (NMDA receptor ) and behaviors in irritable bowel syndrome (IBS) rats. METHODS: Wistar rats were randomly divided into blank control group (blank group, n=10) and model preparation group (n=50); experimental rat model of IBS was established by the "neonatal maternal separation and acetic acid enema" combined with "colorectal distension stimulation" method. A total of 50 IBS rats were randomly assigned to five groups of 10 each: model group, Yintang (GV29) group, Neiguan (PC6) group, Tianshu (ST25) group, and Zusanli (ST36) group. Rats in four treatment groups, aged 9 weeks old, were treated with EA by HANS with a sparse-dense wave with a frequency of 2/100 Hz, current of 0.1-0.3mA, and 20 min/stimulation, every other day for a total of 5 sessions. After treatment, the abdominal visceral sensitivity was evaluated by abdominal withdrawal reflex (AWR), and the psychological and emotional behavior of rats were evaluated by the open-field test (OFT). The expression of NMDA receptors in anterior cingulate cortex (ACC) was detected by Quantitative Real-time PCR, and the positive expression of NMDA receptors in colon was detected by immunohistochemistry. RESULTS: The IBS rat's abdomen is more sensitive and irritable; NR1, NR2A, and NR2B in ACC and NR1 and NR2B in colon of rats significantly increased in the model group versus the normal group (P<0.01) and were inhibited in all treatment groups (P<0.01, P<0.05). Additionally, NR2A and NR2B in ACC reduced more in GV29 group (P<0.01) than in other treatment groups (P all<0.05) compared with the model group. The expression of NR2B in colon was significantly inhibited in ST36 group (P<0.01) and inhibited in GV29 group and ST25 group (P all <0.05) compared with the model group. And the expression of NR2B in colon was more inhibited in ST36 group than in PC6 group (P<0.01). CONCLUSIONS: EA at different acupoints could obviously relieve abdominal pain and abnormal behaviors in IBS rats in different degrees of effects. The effect of abdominal pain-relief, from greatest to least, is ST25, ST36, GV29, and PC6, while the effect of relieving abnormal behaviors caused by IBS, from greatest to least, is GV29, PC6, ST36, and ST25. There are significant differences in the expressions of NMDA receptors in ACC and colon among different acupoints. This difference should be related to the location distribution and indications of acupoints.

ß­Diketonate-Iron(III) Complex: A Versatile Fluorine-19 MRI Signal Enhancement Agent.

Fluorine-19 magnetic resonance imaging (MRI) has gained considerable momentum as a promising imaging modality for in vivo tracking of cellular therapies and as a diagnostic for inflammatory disease. To further the utility of this technique, we increase imaging probe sensitivity by merging paramagnetic metal chelates with aqueous perfluorocarbon (PFC) nanoemulsions. We prepared a highly fluorinated ferric tris(ß-diketonate) chelate (MW = 1265.2 g/mol) at gram scale. This iron chelate is soluble in multiple PFC oils used for MRI and readily reduces the 19F longitudinal relaxation time (T 1) to <100 ms with modest line broadening and displays superior properties for 19F MRI applications. The sensitivity enhancement by Fe(III) laden PFC nanoemulsion was confirmed in MRI phantom studies, where reduced T 1 speeds data acquisition thereby increasing the 19F image sensitivity per time via signal averaging. Additionally, 19F relaxivity of nanoemulsions incorporating other metal ions, including Gd, Er, Ho, Dy, Mn, Cr, and Ni, were evaluated. High-moment lanthanide ions, such as Gd(III), display severe line broadening, but other ions [e.g., Ho(III)] induce pseudocontact chemical shifts (up to 0.5 ppm) of 19F in nanoemulsion, which makes them potentially useful for multichromatic 19F imaging. Formulated nanoemulsions have a shelf life >200 days. Free ß-diketonate or its iron complex in formed PFC nanoemulsion did not induce cytotoxicity in intracellularly labeled macrophages. Overall, ferric tris(ß-diketonate) chelate provides a scalable approach for boosting sensitivity of PFC-based 19F MRI probes. More generally, it can functionalize PFC oil, whose chemical modification remains challenging.

Fluorous-Soluble Metal Chelate for Sensitive Fluorine-19 Magnetic Resonance Imaging Nanoemulsion Probes.

Fluorine-19 MRI is an emerging cellular imaging approach, enabling lucid, quantitative "hot-spot" imaging with no background signal. The utility of 19F-MRI to detect inflammation and cell therapy products in vivo could be expanded by improving the intrinsic sensitivity of the probe by molecular design. We describe a metal chelate based on a salicylidene-tris(aminomethyl)ethane core, with solubility in perfluorocarbon (PFC) oils, and a potent accelerator of the 19F longitudinal relaxation time ( T1). Shortening T1 can increase the 19F image sensitivity per time and decrease the minimum number of detectable cells. We used the condensation between the tripodal ligand tris-1,1,1-(aminomethyl)ethane and salicylaldehyde to form the salicylidene-tris(aminomethyl)ethane chelating agent (SALTAME). We purified four isomers of SALTAME, elucidated structures using X-ray scattering and NMR, and identified a single isomer with high PFC solubility. Mn4+, Fe3+, Co3+, and Ga3+ cations formed stable and separable chelates with SALTAME, but only Fe3+ yielded superior T1 shortening with modest line broadening at 3 and 9.4 T. We mixed Fe3+ chelate with perfluorooctyl bromide (PFOB) to formulate a stable paramagnetic nanoemulsion imaging probe and assessed its biocompatibility in macrophages in vitro using proliferation, cytotoxicity, and phenotypic cell assays. Signal-to-noise modeling of paramagnetic PFOB shows that sensitivity enhancement of nearly 4-fold is feasible at clinical magnetic field strengths using a 19F spin-density-weighted gradient-echo pulse sequence. We demonstrate the utility of this paramagnetic nanoemulsion as an in vivo MRI probe for detecting inflammation macrophages in mice. Overall, these paramagnetic PFC compounds represent a platform for the development of sensitive 19F probes.

[Comparison of effects of electroacupuncture at "Dachangshu" (BL 25) or "Tianshu" (ST 25) on visceral sensitivity, c-kit and TRPV1 of irritable bowel syndrome rats].

OBJECTIVE: To compare the effects of electroacupuncture (EA) at "Dachangshu" (BL 25) or "Tianshu" (ST 25) for visceral sensitivity, gene expression product c-kit of colonic Cajal interstitial cells (ICC) and capsaicin receptor 1 (TRPV1) of irritable bowel syndrome (IBS) rats, so as to investigate the effect and mechanism differences of EA at the back shu point and the front mu point of large intestine for IBS rats. METHODS: Forty-two Wistar neonatal rats were randomly divided into a blank group (9 rats) and a model group (33 rats). IBS model was established with mother and child separation, acetic acid enema in young rats and colorectal dilatation method. Twenty-seven IBS rats in life were randomly divided into a model control group, a Dachangshu group and a Tianshu group, 9 rats in each group. EA (disperse-dense wave, 2 Hz/100 Hz, 0.1-0.3 mA) for 20 min was used at "Dachangshu" (BL 25) and "Tianshu" (ST 25) respectively in the Dachangshu and Tianshu groups, once every other day, totally 5 times. The rats in the model control group were fixed with soft cloth sleeve for 20 min, without acupuncture. No intervention was used in the blank group. The stool property Bristol grading score was recorded before and after intervention in each group. The visceral sensitivity was evaluated by abdominal withdrawal reflex. The latency until the first systolic wave occurred and the number of systolic wave within 90 s were observed. Immunohistochemical was used to detect the positive expressions of c-kit and TRPV1, the ICC colon specific marker. RESULTS: Compared with the blank group, the Bristol score increased，latency period shortened, systolic wave number increased, c-kit and TRPV1 positive expressions increased in the model control group (all P<0.01). Compared with the model control group, the Bristol score decreased, latency period increased, systolic wave number decreased, c-kit and TRPV1 positive expressions decreased after intervention in the Dachangshu and Tianshu groups (P<0.05, P<0.01). Compared with the Dachangshu group, the TRPV1 positive expression decreased after intervention in the Tianshu group (P<0.05). CONCLUSION: EA at "Dachangshu" (BL 25) or "Tianshu"(ST 25) can improve the diarrhea in IBS model rats, reduce the visceral sensitivity, and its mechanism may be related to regulating the expressions of colon c-kit and TRPV1. EA at "Tianshu" (ST 25) is more apparent for TRPV1 than at "Dachangshu" (BL 25).

[Effect of Electroacupuncture at "Yintang" (GV 29) and "Tianshu" (ST 25) on the Ethology and the Expression of TRPV 1 Receptor in Colon of Irritable Bowel Syndrome Rats].

OBJECTIVE: To observe the ethology and expression of transient receptor potential vanilloid-1(TRPV 1) in colon of irritable bowel syndrome (IBS) rats treated by electroacupuncture (EA) at "Yintang" (GV 29) and "Tianshu" (ST 25), so as to explore the different effectiveness of different acupoints and its related mechanism underlying improvement of the symptoms of somatopsychic illness. METHODS: Thirty-two neonatal Wistar rats were randomly divided into blank control group, model group, Yintang (GV 29) group, and Tianshu (ST 25) group (n=8 in each group). IBS model was established by neonatal maternal separation and acetic acid enema combined with colon and rectum expansion stimulation. Rats of the GV 29 and ST 25 groups were given EA treatment at age of 9 weeks old, 20 minutes, once every other day for 5 times. Latency of the 1st time contraction wave and numbers of contractive wave in 90 s were recorded to evaluate abdominal visceral sensitivity by abdominal withdrawal reflex. Horizontal and vertical movements were observed to assess the emotional and psychological behavior of rats by open field test. TRPV 1 expression in colon was detected by immunohistochemistry method. RESULTS: Compared with the black control group, latency of the 1st time contractive wave was significantly shortened and the wave numbers in 90 s were increased significantly in the model group (P<0.01), while the numbers of vertical and horizontal movements were also significantly reduced (P<0.01), accompanied with increased TRPV 1 expression in the colon (P<0.05). Compared with the model group, After EA intervention, the levels of the above-mentioned 5 indexes were significantly reversed in the GV 29 and ST 25 groups (P<0.01,P<0.05), except the number of horizontal movement in the ST 25 group (P>0.05). The expression level of TRPV 1 was significantly lower in the ST 25 group than in the GV 29 group (P<0.01). CONCLUSIONS: EA at GV 29 and ST 25 can alleviate the abdominal pain and improve the mental and emotional disorders in IBS rats. GV 29 has a better effect on relieving the depressive-like psychoemotional behavior of IBS rats, while ST 25 is more effective in treating abdominal pain. There is significantly different influence on TRPV 1 expression in colon between these two treatment groups, which may contribute to their different effect in pain relieving.

Invasive Breast Cancer Preferably and Predominantly Occurs at the Interface Between Fibroglandular and Adipose Tissue.

BACKGROUND: Increasing evidence suggests adipocyte involvement in malignant breast tumor invasive front or margin. The aim of this study was to evaluate the location of invasive breast tumors in relation to fibroglandular and adipose tissue by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). PATIENTS AND METHODS: Pretreatment breast DCE-MRI images of 294 patients with biopsy-proven invasive breast cancer from 2008 to 2014 were studied. Invasive breast tumors were visualized as enhanced lesions in the postcontrast subtraction images. Positive identification of biopsy-confirmed invasive breast tumors on DCE-MRI images was achieved by correlation of findings from breast MRI and pathology reports. Tumor location in relation to fibroglandular and adipose tissue was investigated using precontrast T1-weighted MRI images. RESULTS: Of 294 patients, 291 had DCE-MRI discernable invasive breast tumors located at the interface between fibroglandular and adipose tissues, regardless of the tumor size, type, receptor status, or breast composition. CONCLUSION: Invasive breast cancer preferably and predominantly occurs adjacent to breast adipose tissue.

A preclinical murine model for the early detection of radiation-induced brain injury using magnetic resonance imaging and behavioral tests for learning and memory: with applications for the evaluation of possible stem cell imaging agents and therapies.

Stem cell therapies are being developed for radiotherapy-induced brain injuries (RIBI). Magnetic resonance imaging (MRI) offers advantages for imaging transplanted stem cells. However, most MRI cell-tracking techniques employ superparamagnetic iron oxide particles (SPIOs), which are difficult to distinguish from hemorrhage. In current preclinical RIBI models, hemorrhage occurs concurrently with other injury markers. This makes the evaluation of the recruitment of transplanted SPIO-labeled stem cells to injury sites difficult. Here, we developed a RIBI model, with early injury markers reflective of hippocampal dysfunction, which can be detected noninvasively with MRI and behavioral tests. Lesions were generated by sub-hemispheric irradiation of mouse hippocampi with single X-ray beams of 80 Gy. Lesion formation was monitored with anatomical and contrast-enhanced MRI and changes in memory and learning were assessed with fear-conditioning tests. Early injury markers were detected 2 weeks after irradiation. These included an increase in the permeability of the blood-brain barrier, demonstrated by a 92 ± 20 % contrast enhancement of the irradiated versus the non-irradiated brain hemispheres, within 15 min of the administration of an MRI contrast agent. A change in short-term memory was also detected, as demonstrated by a 40.88 ± 5.03 % decrease in the freezing time measured during the short-term memory context test at this time point, compared to that before irradiation. SPIO-labeled stem cells transplanted contralateral to the lesion migrated toward the lesion at this time point. No hemorrhage was detected up to 10 weeks after irradiation. This model can be used to evaluate SPIO-based stem cell-tracking agents, short-term.

Association between breast cancer, breast density, and body adiposity evaluated by MRI.

OBJECTIVE: Despite the lack of reliable methods with which to measure breast density from 2D mammograms, numerous studies have demonstrated a positive association between breast cancer and breast density. The goal of this study was to study the association between breast cancer and body adiposity, as well as breast density quantitatively assessed from 3D MRI breast images. METHODS: Breast density was calculated from 3D T1-weighted MRI images. The thickness of the upper abdominal adipose layer was used as a surrogate marker for body adiposity. We evaluated the correlation between breast density, age, body adiposity, and breast cancer. RESULTS: Breast density was calculated for 410 patients with unilateral invasive breast cancer, 73 patients with ductal carcinoma in situ (DCIS), and 361 controls without breast cancer. Breast density was inversely related to age and the thickness of the upper abdominal adipose layer. Breast cancer was only positively associated with body adiposity and age. CONCLUSION: Age and body adiposity are predictive of breast density. Breast cancer was not associated with breast density; however, it was associated with the thickness of the upper abdominal adipose layer, a surrogate marker for body adiposity. Our results based on a limited number of patients warrant further investigations. KEY POINTS: • MRI breast density is negatively associated with body adiposity. • MRI breast density is negatively associated with age. • Breast cancer is positively associated with body adiposity. • Breast Cancer is not associated with MRI breast density.

Imaging transplanted stem cells in real time using an MRI dual-contrast method.

Stem cell therapies are currently being investigated for the repair of brain injuries. Although exogenous stem cell labelling with superparamagnetic iron oxide nanoparticles (SPIONs) prior to transplantation provides a means to noninvasively monitor stem cell transplantation by magnetic resonance imaging (MRI), monitoring cell death is still a challenge. Here, we investigate the feasibility of using an MRI dual-contrast technique to detect cell delivery, cell migration and cell death after stem cell transplantation. Human mesenchymal stem cells were dual labelled with SPIONs and gadolinium-based chelates (GdDTPA). The viability, proliferation rate, and differentiation potential of the labelled cells were then evaluated. The feasibility of this MRI technique to distinguish between live and dead cells was next evaluated using MRI phantoms, and in vivo using both immune-competent and immune-deficient mice, following the induction of brain injury in the mice. All results were validated with bioluminescence imaging. In live cells, a negative (T2/T2*) MRI contrast predominates, and is used to track cell delivery and cell migration. Upon cell death, a diffused positive (T1) MRI contrast is generated in the vicinity of the dead cells, and serves as an imaging marker for cell death. Ultimately, this technique could be used to manage stem cell therapies.

Noninvasive Imaging of Liposomal Delivery of Superparamagnetic Iron Oxide Nanoparticles to Orthotopic Human Breast Tumor in Mice.

PURPOSE: Magnetic resonance imaging (MRI) is widely used for diagnostic imaging in preclinical studies and in clinical settings. Considering the intrinsic low sensitivity and poor specificity of standard MRI contrast agents, the enhanced delivery of MRI tracers into tumors is an important challenge to be addressed. This study was intended to investigate whether delivery of superparamagnetic iron oxide nanoparticles (SPIONs) can be enhanced by liposomal SPION formulations for either "passive" delivery into tumor via the enhanced permeability and retention (EPR) effect or "active" targeted delivery to tumor endothelium via the receptors for vascular endothelial growth factor (VEGFRs). METHODS: In vivo MRI of orthotopic MDA-MB-231 tumors was performed on a preclinical 9.4 T MRI scanner following intravenous administration of either free/non-targeted or targeted liposomal SPIONs. RESULTS: In vivo MRI study revealed that only the non-targeted liposomal formulation provided a statistically significant accumulation of SPIONs in the tumor at four hours post-injection. The EPR effect contributes to improved accumulation of liposomal SPIONs in tumors compared to the presumably more transient retention during the targeting of the tumor vasculature via VEGFRs. CONCLUSIONS: A non-targeted liposomal formulation of SPIONs could be the optimal option for MRI detection of breast tumors and for the development of therapeutic liposomes for MRI-guided therapy.

Magnetic resonance imaging contrast of iron oxide nanoparticles developed for hyperthermia is dominated by iron content.

PURPOSE: Magnetic iron oxide nanoparticles (MNPs) are used as contrast agents for magnetic resonance imaging (MRI) and hyperthermia for cancer treatment. The relationship between MRI signal intensity and cellular iron concentration for many new formulations, particularly MNPs having magnetic properties designed for heating in hyperthermia, is lacking. In this study, we examine the correlation between MRI T2 relaxation time and iron content in cancer cells loaded with various MNP formulations. MATERIALS AND METHODS: Human prostate carcinoma DU-145 cells were loaded with starch-coated bionised nanoferrite (BNF), iron oxide (Nanomag® D-SPIO), Feridex™, and dextran-coated Johns Hopkins University (JHU) particles at a target concentration of 50 pg Fe/cell using poly-D-lysine transfection reagent. T2-weighted MRI of serial dilutions of these labelled cells was performed at 9.4 T and iron content quantification was performed using inductively coupled plasma mass spectrometry (ICP-MS). Clonogenic assay was used to characterise cytotoxicity. RESULTS: No cytotoxicity was observed at twice the target intracellular iron concentration (∼100 pg Fe/cell). ICP-MS revealed highest iron uptake efficiency with BNF and JHU particles, followed by Feridex and Nanomag-D-SPIO, respectively. Imaging data showed a linear correlation between increased intracellular iron concentration and decreased T2 times, with no apparent correlation among MNP magnetic properties. CONCLUSIONS: This study demonstrates that for the range of nanoparticle concentrations internalised by cancer cells the signal intensity of T2-weighted MRI correlates closely with absolute iron concentration associated with the cells. This correlation may benefit applications for cell-based cancer imaging and therapy including nanoparticle-mediated drug delivery and hyperthermia.

Heterogeneity of tumor vasculature and antiangiogenic intervention: insights from MR angiography and DCE-MRI.

PURPOSE: Solid tumor vasculature is highly heterogeneous, which presents challenges to antiangiogenic intervention as well as the evaluation of its therapeutic efficacy. The aim of this study is to evaluate the spatial tumor vascular changes due to bevacizumab/paclitaxel therapy using a combination approach of MR angiography and DCE-MRI method. EXPERIMENTAL DESIGN: Tumor vasculature of MCF-7 breast tumor mouse xenografts was studied by a combination of MR angiography and DCE-MRI with albumin-Gd-DTPA. Tumor macroscopic vasculature was extracted from the early enhanced images. Tumor microvascular parameters were obtained from the pharmacokinetic modeling of the DCE-MRI data. A spatial analysis of the microvascular parameters based on the macroscopic vasculature was used to evaluate the changes of the heterogeneous vasculature induced by a 12 day bevacizumab/paclitaxel treatment in mice bearing MCF-7 breast tumor. RESULTS: Macroscopic vessels that feed the tumors were not affected by the bevacizumab/paclitaxel combination therapy. A higher portion of the tumors was within close proximity of these macroscopic vessels after the treatment, concomitant with tumor growth retardation. There was a significant decrease in microvascular permeability and vascular volume in the tumor regions near these vessels. CONCLUSION: Bevacizumab/paclitaxel combination therapy did not block the blood supply to the MCF-7 breast tumor. Such finding is consistent with the modest survival benefits of adding bevacizumab to current treatment regimens for some types of cancers.

Bioorthogonal, two-component delivery systems based on antibody and drug-loaded nanocarriers for enhanced internalization of nanotherapeutics.

Nanocarriers play an important role in targeted cancer chemotherapy. The optimal nanocarrier delivery system should provide efficient and highly specific recognition of the target cells and rapid internalization of the therapeutic cargo to reduce systemic toxicity as well as to increase the cytotoxicity to cancer cells. To this end, we developed a two-step, two-component targeted delivery system based on antibody and drug-loaded nanocarrier that uses bioorthogonal click reactions for specific internalization of nanotherapeutics. The pretargeting component, anti-HER2 humanized monoclonal antibody, trastuzumab, functionalized with azide groups labels cancer cells that overexpress HER2 surface receptors. The drug carrier component, dibenzylcyclooctyne substituted albumin conjugated with paclitaxel, reacts specifically with the pretargeting component. These two components form cross-linked clusters on the cell surface, which facilitates the internalization of the complex. This strategy demonstrated substantial cellular internalization of clusters consisted of HER2 receptors, modified trastuzumab and paclitaxel-loaded albumin nanocarriers, and subsequent significant cytotoxicity in HER2-positive BT-474 breast cancer cells. Our results show high efficacy of this strategy for targeted nanotherapeutics. We foresee to broaden the applications of this strategy using agents such as radionuclides, toxins, and interfering RNA.

Water exchange-minimizing DCE-MRI protocol to detect changes in tumor vascular parameters: effect of bevacizumab/paclitaxel combination therapy.

OBJECTIVE: The purpose of this study was to assess changes in the tumor microvasculature induced by combination antiangiogenic therapy in MCF-7 breast tumor mouse models, using a noninvasive DCE-MRI method that minimizes the effect of water exchange. MATERIALS AND METHODS: 3D quantitative DCE-MRI images were acquired with a heavily T1-weighted saturation recovery gradient echo sequence with a recovery delay of 20 ms. Tumor vascular volume (VV) and vascular permeability-surface area product (PS) were obtained through a linear regression of the albumin-Gd-DTPA-enhanced dynamic image intensity on MCF-7 breast tumor mouse models treated with combination bevacizumab/paclitaxel therapy. RESULTS: Measured tumor VV values were significantly higher than the values that have been reported previously using quantitative T1 mapping, and are in good agreement with micro-CT (computed tomography) results reported earlier from other tumor models. A trend of decreasing tumor PS was detected in the group of MCF-7 tumor bearing mice treated with the bevacizumab/paclitaxel combination regimen. CONCLUSION: VV and PS maps obtained by a heavily T1-weighted acquisition protocol revealed the large peripheral blood vessels as well as the permeable areas within the tumor. A 12-day/three-dose combination treatment of bevacizumab and paclitaxel resulted in delayed tumor growth and a trend of decreasing tumor vascular permeability surface area product.

[Effect of acupuncture at different time points on kidney function and oxygen free radical metabolism in rats with simulated weightlessness].

OBJECTIVE: To explore the effects of pre-acupuncture and immediate acupuncture on kidney function and oxygen free radical metabolism in rats with simulated weightlessness. METHODS: Twenty male clean-grade Wister rats were randomly divided into a normal control group, a model group, a pre-acupuncture group and an immediate acupuncture group, 5 rats in each one. The rats in the normal control group did not receive any treatment but free activities for 4 weeks. The rats in the rest groups received 4-week tail suspension to establish the model of simulated weightlessness. One week before the tail suspension, the rats in the pre-acupuncture group were treated with electroacupuncture at "Shenshu" (BL 23), "Pishu" (BL 20) and "Sanyinjiao" (SP 6) for 30 min per treatment, once a day for 7 days. The rats in the immediate acupuncture group received tail suspension and acupuncture at the same time; during the tail suspension, the electroacupuncture was applied at "Shenshu" (BL 23), "Pishu" (BL 20) and "Sanyinjiao" (SP 6) for 30 min per treatment, once every other day for 14 days. The colorimetric method was used to measure the content of blood urea nitrogen (BUN) in serum as well as activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) and content of malonaldehyde (MDA) in renal tissue in each group. RESULTS: Compared with the normal control group, the content of BUN in the model group was increased significantly (P<0.01), the activity of SOD and GSH-PX in nephridial tissue was significantly reduced (both P<0.01), and the content of MDA was increased significantly (P<0.05). Compared with the model group, the content of BUN in the pre-acupuncture group and immediate acupuncture group was significantly reduced (P<0.01, P<0.05), the activity of GSH-PX in the pre-acupuncture group was obviously increased (P<0.05) and the content of MDA in the immediate acupuncture group was increased significantly (P<0.01). Compared with the immediate acupuncture group, the content of MDA in the pre-acupuncture group was lower (P<0.01). CONCLUSION: The pre-acupuncture and immediate acupuncture both have the capacity to improve the kidney function and anti-oxygen free radical injury in rats with simulated weightlessness, however, the capacity to increase the protection ability of the kidney and eliminate free radical in the pre-acupuncture group is superior to that in the immediate acupuncture group, which is likely to be related with improving antioxidant ability of kidney.